Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

Abstract

Seizures are a common presenting symptom during viral infections of the central nervous system (CNS) and can occur during the initial phase of infection (“early” or acute symptomatic seizures), after recovery (“late” or spontaneous seizures, indicating the development of acquired epilepsy), or both. The development of acute and delayed seizures may have shared as well as unique pathogenic mechanisms and prognostic implications. Based on an extensive review of the literature, we present an overview of viruses that are associated with early and late seizures in humans. We then describe potential pathophysiologic mechanisms underlying ictogenesis and epileptogenesis, including routes of neuroinvasion, viral control and clearance, systemic inflammation, alterations of the blood-brain barrier, neuroinflammation, and inflammation-induced molecular reorganization of synapses and neural circuits. We provide clinical and animal model findings to highlight commonalities and differences in these processes across various neurotropic or neuropathogenic viruses, including herpesviruses, SARS-CoV-2, flaviviruses, and picornaviruses. In addition, we extensively review the literature regarding Theiler’s murine encephalomyelitis virus (TMEV). This picornavirus, although not pathogenic for humans, is possibly the best-characterized model for understanding the molecular mechanisms that drive seizures, epilepsy, and hippocampal damage during viral infection. An enhanced understanding of these mechanisms derived from the TMEV model may lead to novel therapeutic interventions that interfere with ictogenesis and epileptogenesis, even within non-infectious contexts.

Brain-Derived Neurotrophic Factor Inhibits the Function of Cation-Chloride Cotransporter in a Mouse Model of Viral Infection-Induced Epilepsy

“…However, animal models of TLE caused by infection are limited. Furthermore, high mortality rate and low rate of epilepsy development in majority of these models curtail their utility (Patel and Wilcox, 2017;Löscher and Howe, 2022). In contrast, TMEV-infected C57BL/6J mice exhibit acute seizures during active infection, survive the initial infection, exhibit hippocampal neuropathology and gliotic scar, develop behavioral comorbidities such as anxiety and cognitive impairment, and develop epilepsy after about 2-3 months post-infection (Libbey et al, 2008;Stewart et al, 2010a;Umpierre et al, 2014;Broer et al, 2016;Lawley et al, 2021).…”

“…It is likely based on this finding that uncoupling PLCγ1 from the activated TrkB alone using pY816 could be insufficient to ameliorate the reduction of KCC2 and suppress TMEV-induced seizures. Lastly, since excessive inflammatory reaction post-TMEV infection is a major driver for the development of seizures in this model (Löscher and Howe, 2022), it is likely that inhibiting BDNF signaling mediated through PLCγ1 alone may not have significant anticonvulsant effects.…”

“…Epilepsy is a devastating neurological disorder affecting around 50 million people worldwide showing a higher prevalence in low/ middle-income countries (LMIC) (Beghi, 2020). In these countries in particular, viral infection of the central nervous system (CNS) is a common cause of acquired temporal lobe epilepsy (TLE) for which there is currently no effective antiepileptic treatment for patients at risk (Patel and Wilcox, 2017;Löscher and Howe, 2022). Over two dozen antiseizure drugs are clinically approved that target primarily excitatory and inhibitory neurotransmission.…”

Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?

“…Furthermore, toxic effects of ivermectin off‐label use for COVID‐19 have been described, including severe episodes of confusion, ataxia, seizures, and hypotension 22 . Such toxicity can be due to either the high doses of ivermectin used or the impairment of the BBB due to the infection 100 . Seizures also impair the functionality of the BBB, 65 but it is not known whether this increases the toxicity of ivermectin.…”

Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models

“…Concerning animal models of epilepsy induced by viral encephalitis, comorbidities have been reported for a mouse model using Theiler's murine encephalomyelitis virus (TMEV) for induction of seizures and epilepsy 136 . The TMEV model in C57BL/6 mice is the most widely used model of seizures and epilepsy developing after viral encephalitis 136 .…”